5-(3-formylamino-4-hydroxyphenyl)-3-(1-(4-methoxyphenyl)prop-2-yl)-oxazolidines

ABSTRACT

The present invention relates to novel oxazolidines of formula (1) ##STR1## wherein R 1  and R 2  are simultaneously hydrogen or both are the same lower alkyl radical or together are 4- to 7-membered lower alkylene, and to the salts thereof in racemic and chiral form, to the preparation of these novel compounds, to pharmaceutical compositions containing them and to the use thereof as medicaments. The compounds have a stimulating effect on beta-adrenergic receptors and can be used, inter alia, for the treatment of diseases associated with reversible obstruction of the respiratory tract, typically asthma and chronic bronchitis, and also for inflammations of different origin.

The present invention relates to novel oxazolidines of formula (1)##STR2## wherein R₁ and R₂ are simultaneously hydrogen or both are thesame lower alkyl radical or together are 4- to 7-membered loweralkylene, and to the salts thereof in racemic and chiral form, to thepreparation of these novel compounds, to pharmaceutical compositionscontaining them and to the use thereof as medicaments.

U.S. Pat. No. 4,407,819 (American Cyanimide Co.) discloses oxazolidineswhich differ in the orientation of the substituents at the phenyl ringand in the substituents at the oxygen atom in the oxazolidine ring, andwhich are used as additives for animal feeds.

Throughout this specification, radicals and compounds qualified by theterm "lower" will be understood as meaning those that carry up to 7,preferably up to 4, carbon atoms inclusive.

Lower alkyl is typically C₁ -C₄ alkyl such as methyl, ethyl, propyl orbutyl.

4- to 7-Membered lower alkylene is preferably 1,4-butylene,1,5-pentylene, 1,6-hexylene, and also 1,7-heptylene.

The novel compounds thus comprise all enantiomers, diastereoisomers andtheir mixtures, including their racemates. Compounds of formula I withinthe scope of this invention are preferably in the form of racemates ofpossible stereoisomers (R,R and S,S), but more preferably in chiralforms R,R and S,S.

Salts of compounds of formula I are preferably pharmaceuticallyacceptable salts, typically acid addition salts, which are formed, interalia, with strong inorganic acids such as mineral acids, e.g. sulfuricacid, a phosphoric acid or a hydrohalic acid, with strong organiccarboxylic acids such as lower alkanecarboxylic acids, typically aceticacid, or with dicarboxylic acids or unsaturated dicarboxylic acids suchas malonic acid, maleic acid or furmaric acid, or with hydroxycarboxylicacids such as tartaric or citric acid, or with sulfonic acids such aslower alkanesulfonic acids or benzenesulfonic acids or substitutedbenzenesulfonic acids such as methane or p-toluenesulfonic acid, orsalts with bases, typically alkali metal or alkaline earth metal salts,e.g. sodium, potassium or magnesium salts, pharmaceutically acceptabletransition metal salts such as zinc or copper salts, or salts withammonia or organic amines, including cyclic amines such as mono-, di- ortri-lower alkylamines, typically hydroxy-lower alkylamines, e.g. mono-,di- or tri-hydroxy-lower alkylamines, hydroxy-lower alkyl-loweralkylamines or polyhydroxy-lower alkylamines. Cyclic amines aretypically morpholine, thiomorpholine, piperidine or pyrrolidine.Suitable mono-lower alkylamines typically include ethyl- andtert-butylamine, and suitable di-lower alkylamines are typicallydiethyl- and diisopropylamine, and suitable tri-lower alkylamines aretypically trimethyl- and triethylamine. Corresponding hydroxy-loweralkylamines are typically mono-, di- and triethanolamine; hydroxy-loweralkyl-lower alkylamines are typically N,N-dimethylaminoethanol andN,N-diethylaminoethanol; a suitable polyhydroxy-lower alkylamine isglucosamine. Unsuitable salts are also included for pharmaceuticalusages, as these may be used, inter alia, for the isolation and/orpurification of free compounds of formula I and their pharmaceuticallyacceptable salts.

The compounds of formula I and their pharmaceutically acceptable saltshave valuable pharmacological properties.

The novel compounds of formula I have a prolonged stimulating action onbeta-adrenergic receptors or they induce relaxation of sensitiveunstriated muscles.

Owing to this effective relaxation of unstriated muscles, the compoundsof formula I can be used for the prevention or treatment of bronchialspasm and dispnoe in diseases such as bronchial asthma, chronicbronchitis and chronic obstructive pulmonary diseases, anaphylacticbronchial spasm and cystic fibrosis as well as for the prevention oralleviation of premature labour pains in a stage of pregnancy.

The compounds of formula I are also useful for the prevention ortreatment of inflammatory conditions in a variety of diseases,especially where the activation of beta-adrenergic receptors influencesthe course of the disease.

In particular, the compounds of formula I are suitable for preventing orlimiting the release of preformed or newly synthesised inflammationtransmitters of cellular degranulation products and reactive oxygencompounds of cells such as mast cells, macrophages, basophilic cells,eosinophilic cells and lymphocytes.

The compounds of formula I induce an antiinflammatory action bypreventing or limiting the release of phlogogens such as histamine,leucotrienes, basic and cationic proteins, tryptanes and chymase,cytokines and the like, and are suitable for the treatment of chronicand acute urticaria, psoriasis, allergic conjunctivitis, acinitis, hayfever, mastocytosis and the like.

By activating endothelial beta-adrenergic receptors the novel compoundsare also suitable for preventing or alleviating the consequences andinjury caused by increased microvascular permeability and may be used,inter alia, for inflammations caused by inflammation transmitters,surgical operations, injuries, burns and radiation injury. The compoundsare therefore suitable for the treatment of diseases that are associatedwith obstruction of the respiratory tract such as asthma, chronicbronchitis and other pulmonary diseases, intumescences, extravasationsresulting from surgical operations, chemical injuries, burns and alsoradiation injury such as cerebral oedema and other injury resulting fromradiotherapy. By activating the signal transduction mechanism which iscoupled to beta-adrenergic receptors, for example adenylyl cyclase (butnot restricted thereto), the novel compounds prevent the production ofcytokines, lymphokines and also monoldnes whose synthesis is regulatedby easily influenced signal transduction elements, and they aretherefore suitable for the treatment of diseases in which proteinsparticipate as transmitters in the course of the disease, includingasthma, septicaemia, inflammations, certain immunological processes andthe like.

The compounds of formula I induce a useful relaxation of a smooth muscleof the bronchia, of the uterus, of the vascular system and the like.

This relaxation can be detected as follows: in segments which were takenfrom the ileum of a guinea pig weighing 300-400 g and incubated in anorgan bath in tyrode solution at 38° C. and gassed with a mixture of 95%oxygen and 5% carbon dioxide at a load of 1 g, contractions are inducedwith synthetic leucotriene D₄ (in potassium salt form) or histaminePGE₂α, thromboxane mimetica or BaCl₂ (as depolarising solution) andregistered isotonically. The degree of inhibition of the contractions bythe test compound is determined after a preliminary incubation of 2minutes in the form of the IC₅₀, which denotes the concentration atwhich the test contractions are reduced by 50%.

The compounds of formula I have an extremely prolonged action andexhibit excellent activity in vivo. For example, in abronchoconstriction standard assay using guinea pigs, a pronounced LTD₄-antagonistic effect may be observed on administration of an aerosolsolution containing c. 0.00001 to c. 1% by weight of test compound. Inthis test model, male guinea pigs of 400-700 g body weight areanaesthetised intraperitoneally with 1.4 g/kg of urethane and apolyethylene cannula is inserted into the jugular vein. A secondpolyethylene cannula is inserted into the trachea. Pressure in theoesophagus is recorded by means of a cannula inserted into theoesophagus and connected to a Starham pressure transducer. The animal isplaced in an airtight plexiglass chamber which is connected to a No. 000Fleisch's tube and a Validyne transducer MP 45-1. The flow is measuredwith this assembly. After the surgical preparation of the test animals,a certain period of time is allowed to elapse so as to allow thepulmonary functions to stabilise. The test compound is then administeredin accordance with the following procedure. The test animals are exposedfor one minute to a 1% (weight/volume) aerosol solution of the testcompound or to distilled water (for control purposes). For all the testcompounds that are administered by inhalation, a Monaghan ultrasoundspray apparatus (model 670) of which the particle size varies between 1and 8 microns, the majority being 3 microns, is used. Aqueous solutionsare freshly prepared each time and are introduced into the chamber ofthe spray device using an on-stream drug vial. The spray mist producedis administered to the test animals via a glass chamber of 65 mlcapacity which is connected to the trachea by a cannula. At the end ofthe treatment period, LTD₄ (0.3 μg/ml) is administered over a period of2 minutes using a second Monaghan ultrasound spray apparatus (model 670)and via a similar glass chamber. The reduction in compliance is read offin the third minute after the LTD₄ administration and the average valueof three animals is compared with the average value of three controlanimals and the percentage inhibition of compliance (% inhibition) iscalculated in accordance with the following formula: ##EQU1##

If different concentrations of active ingredient are tested, thepercentage inhibition for each concentration is recorded, the "logconcentration" on the abscissa being plotted against the "percentageinhibition" on the ordinate. The IC₅₀ is then determined by linearregression analysis.

The compounds of formula I and their pharmaceutically acceptable saltsalso have the specific and therapeutically very significant advantage ofa relatively long duration of efficacy.

Preferred compounds of formula I within the scope of this invention arethose wherein R₁ and R₂ are simultaneously hydrogen or both are the samelower alkyl radical or together are 4- to 5-membered lower alkylene, andtheir salts in racemic and chiral form.

Particularly preferred compounds of formula I within the scope of thisinvention are those wherein R₁ and R₂ are simultaneously hydrogen orboth simultaneously are methyl or ethyl, and the pharmaceuticallyacceptable salts thereof in racemic and chiral form.

Most preferred compounds of formula I within the scope of this inventionare those wherein R₁ and R₂ are simultaneously hydrogen, and thepharmaceutically acceptable salts thereof in racemic and chiral form.

Specifically preferred within the scope of this invention is theracemate obtained in Example 1 of (5R)-5-(3-formylamino-4-hydroxyphenyl)-3-[(2R)-1-(4-methoxyphenyl)prop-2-yl]-oxazolidineand (5S)-5-(3-formylamino-4-hydroxyphenyl)-3-[(2S)-1-(4-methoxyphenyl)prop-2-yl]oxazolidine or the enantiomers in pure form, or apharmaceutically acceptable salt thereof.

The invention further relates to a process for the preparation ofcompounds of formula I and the salts thereof, which comprises reacting acompound of formula II ##STR3## with a compound of formula III ##STR4##in free and acetalised or ketalised form, wherein R₁ and R₂ are asdefined for formula I.

The condensation of the compounds of formula II with compounds offormula III is carried out in conventional manner in a protic or aproticsolvent such as an aliphatic hydrogen halide, conveniently in adichloroalkane, preferably methylene chloride, or an aliphatic orcycloaliphafic ether, e.g. in tetrahydrofuran or also dioxane. Othersuitable solvents include acetonitrile, ethanol and toluene.

The substances are reacted in the temperature range from -10° to +60°C., preferably from 0° to +30° C., conveniently in the presence of acatalyst, an acid condensing agent, typically an ammonium salt such asammonium acetate. The starting material of formula II is known and itspreparation is described in DE patent 2 305 092 "(corresponding to U.S.Pat. No. 3,994,974)".

The compounds are formula HI are likewise known and described in alltextbooks of chemistry as belonging to the stock of common knowledge.

Compounds obtainable by the process of this invention can be convertedin conventional manner into compounds of formula I.

Salts of compounds of formula I can be converted in a manner known perse into the free compounds, conveniently by treatment with a base suchas an alkali metal hydroxide, a metal carbonate or hydrogencarbonate, orwith another salt-forming base referred to at the outset or with anacid, typically a mineral acid, as with hydrochloric acid, or withanother salt-fondling acid referred to at the outset.

Salts of compounds of formula I can be converted in a manner known perse into other salts, conveniently by treatment with a suitable metalsalt, typically a sodium, barium or silver salt, of another acid in asuitable solvent in which a resultant inorganic salt is insoluble and isthus eliminated from the equilibrium of reaction, and salts of bases bygenerating the free acid and repeated salt-formation.

The compounds of formula I, including their salts, may also be obtainedin the form of hydrates or include the solvent used for crystallisation.

Because of the close relationship between the novel compounds in thefree form and in the form of their salts, the references made throughoutthis specification to the free compounds and their salts will also applyby analogy to the corresponding salts and free compounds.

Depending on the choice of starting materials and procedures, thecompounds of formula I and their salts may be obtained in the form ofone of the mixtures of diastereoisomers, racemates and enantiomers or asmixtures thereof.

Racemates are separated into the individual enantiomers by columnchromatography via a chiral stationary phase.

Racemates can also be separated by known methods into the opticalantipodes, conveniently by recrystallisation from an optically activesolvent, with the aid of micro-organisms or by reacting the mixture ofdiastereoisomers or racemate with an optically active compound, e.g.depending on the acid, basic or functionally modifiable groups presentin the compound of formula I, with an optically active acid, base or anoptically active alcohol, into mixtures of diastereoisomeric salts orfunctional derivatives such as esters, separating these into thediastereoisomers from which the respective desired enantiomer can be setfree in the respective usual manner. Bases, acids or alcohols suitablefor the purpose are typically optically active alkaloid bases such asstrychine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine,3-pipecoline, ephedrine, amphetamine or similar bases which areobtainably by synthesis, optically active carboxylic or sulfonic acidssuch as quinic acid or D- or L-tartaric acid, D- orL-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid orD- or L-camphorsulfonic acid, or optically active alcohols such asborneol or D- or L-(1-phenyl)ethanol.

The invention relates also to those embodiments of the process in whicha compound obtainable as intermediate in any stage of the process isused as starting material and the remaining steps are carried out, or astarting material is used in the form of a derivative or a salt or,especially, is formed under the reaction conditions.

The invention also relates to the novel starting materials which havebeen specially developed for the preparation of the novel compounds,especially those which result in the compounds I described at thebeginning as being especially preferred, to processes for theirpreparation and to the use thereof as intermediates.

The pharmaceutical compositions of this invention which contain thecompound of formula I or a pharmaceutically acceptable salt thereof arethose for enteral, e.g. oral, and also rectal and parenteraladministration to warm-blooded animals, and they contain thepharmacologically active compound alone or together with apharmaceutically acceptable carrier. The daily dose will depend on theage, sex and individual condition of the patient as well as on the modeof administration.

The compounds of formula I can be formulated for administration in anysuitable manner. The invention relates to medicaments which contain atleast one compound of formula I or a physiologically acceptable saltthereof and which are formulated for use in human or veterinarymedicine. Such compositions may be formulated together withphysiologically acceptable carriers or excipients and with additionaloptional medicaments.

The compounds of formula I can be formulated for administration byinhalation or insufflation, or for oral, buccal, parenteral, topical(including nasal) or rectal administration. Administration by inhalationor insufflation is preferred.

For administration by inhalation, the compounds of formula I areconveniently used in the form of a pressurised aerosol spray pack usinga suitable propellant gas.

Such propellant gases or gas mixtures are known per se for thepreparation of pharmaceutical aerosols, and typically include saturatedhydrocarbons such as n-propane, n-butane or isobutane or n-fixturesthereof or partially fluorinated or completely fluorinated(perfluorinated) hydrocarbons.

Partially fiuorinated hydrocarbons are derived from aliphatichydrocarbons containing preferably 1 to 4 carbon atoms, typicallymethane, ethane, propane, n-butane or isobutane, or cycloaliphatichydrocarbons containing preferably 3 and 4 carbon atoms, typicallycyclopropane or cyclobutane, the hydrogen atoms being substituted by atleast one fluorine atom and, preferably, at least two fluorine atoms,such that at least one hydrogen atom and thus one hydrocarbon bondremains in the molecule.

Completely fluorinated (perfluorinated) hydrocarbons are derived fromthe above mentioned aliphatic hydrocarbons of 1 to 4 carbon atoms andthe cycloaliphatic hydrocarbons of 3 to 4 carbon atoms by substitutionof the hydrogen atoms by fluorine atoms.

Suitable partially or completely fluorinated hydrocarbons are typicallymethane derivatives containing 1 to 4, ethane derivatives containing 1to 6, propane derivatives containing 1 to 8, n-butane derivativescontaining 1 to 10, cyclopropane derivatives containing 1 to 6 andcyclobutane derivatives containing 1 to 8, fluorine atoms. In thesepartially or completely fluorinated hydrocarbons the hydrogen atoms arein different positions of the hydrocarbon molecule. The followingpossibilities of isomerism exist for partially fiuorinated hydrocarbons:

If there is only one hydrogen atom in the hydrocarbon molecule, inpropane and butane derivatives it may be in terminal position or at aconnecting member of the carbon chain.

Where the hydrocarbon molecule contains more than one hydrogen atom,still further possibilities of isomerism exist for ethane, propane,n-butane, cyclopropane and cyclobutane derivatives as well as forhydrocarbons containing a greater number of carbon atoms. The hydrogenatoms may be partially or completely in terminal position and bepartially or completely at one member or at different connecting membersof the carbon chains. "Mixed" possibilities of isomerism are alsopossible, where the hydrogen atoms of aliphatic derivatives aredifferently distributed on the terminal carbon atoms and on the same ordifferent connecting members of the carbon chain or are on the same ordifferent carbon ring members of cycloaliphatic derivatives.

It is common practice to use code designations to abbreviate thecustomary nomenclature and to distinguish between the partiallyfluorinated hydrocarbons as well as the completely fluorinatedhydrocarbons referred to hereinafter. These code designations areexplained in Pharmazeutische Technologie, H. Sucker, P. Fuch, P. Speiser(Editor), Thieme Verlag, D-7000 Stuttgart 1978, on page 735, and arelikewise applicable to CFCs. It is customary to use suffixes with theletters a, b . . . for the numerous possibilities of isomerism referredto.

Preferred partially fluorinated hydrocarbons are tetrafluoroethane (134and 134a), trifluoroethane (143a), difluoroethane (152 and 152a) andheptafluoropropane (227).

Alternatively, the compounds of formula I for administration byinhalation or insufflation may be in the form of a dry powder,conveniently as powder mixture, of the compound and a suitable powderbase material such as lactose or starch. The powder mixture can be inunit dose form, typically in the form of capsules or cartridges of e.g.gelatin, or in the form of blister packs from which the powder can bereleased by mans of an inhaler or an insufflater.

For oral administration, the pharmaceutical compositions may typicallybe in the form of tablets, capsules, powders, solutions, syrups orsuspensions which are prepared by known methods with acceptable diluentsor medicinal carriers. For buccal administration, the composition may bein the form of tablets, drops or lozenges, which are prepared in knownmanner.

The compounds of formula I can also be administered parenterally.Compositions for injection may be in unit dose form in ampoules or inmultiple dosage containers with added preservatives. The fomulations maybe in the form of suspensions, solutions or emulsions in oil or aqueousvehicles and can contain adjuvants such as suspending agents,stabilisers and/or dispersants. Alternatively, prior to use the activecompound may be in powder form for reconstitution with a suitablecarrier, typically sterilised, pyrogen-free water.

For topical application, the pharmaceutical compositions of thisinvention may be in the form of ointments, lotions or creams which areprepared in per se known manner, conveniently with an aqueous or oilybase, normally by adding suitable thickeners and/or solvents. For nasalapplication, the compositions can be in the form of a spray which may beprepared as an aqueous solution or suspension or as an aerosol with asuitable propellant.

The compounds of formula I can also be in the form of compositions forrectal administration such as suppositories or retention enemas,conveniently those that contain suppository bases such as cocoa butteror other glycerides.

If the pharmaceutical compositions are prescribed for oral, buccal,rectal or topical administration, they may be associated in per se knownmanner with dosage forms that permit a controlled or delayed release.

The contemplated daily dose of active compound for oral administrationin the treatment of humans is 10 to 500 μg, which may suitably beadministered as a single dose. The exact dose will naturally depend onthe age and condition of the patient and on the mode of administration.Suitable doses for administration by inhalation (aerosols) or nasalapplication are from 1-200 μg, for rectal administration from 10 to 500μg, for intravenous administration from 0.01 to 100 μg, and for topicalapplication from 1 to 1000 μg.

The following Examples will serve to illustrate the invention. Pressuresare given in millibars.

EXAMPLE 1

With stirring, 1.0 ml of 36.5% aqueous formaldehyde is added at roomtemperature to a suspension of 2.75 g of2'-hydroxy-5'-[(RS)-1-hydroxy-2-[[(RS)-p-methoxy-α-methylphenylethyl]amino]ethyl]formanilide(racemic mixture of R,R- and S,S-enantiomers) in 80 ml of methylenechloride. The mixture is stirred for 30 minutes, whereupon a solutionforms. The solution is stirred for a further 15 hours at 26° C. Theprecipitated crystals are isolated by filtration, washed with a smallamount of methylene chloride and dried at 40° C./0.1 mbar for 15 hours.After recrystallisation from ethyl acetate, the racemate of(5R)-5-(3-formylamino-4-hydroxyphenyl)-3-[(2R)-1-(4-methoxyphenyl)prop-2-yl]oxazolidineand(5S)-5-(3-formylamino-4-hydroxyphenyl)-3-[(2S)-1-(4-methoxyphenyl)prop-2-yl]oxazolidinemelts at 87°-92° C., [¹ H-NMR (400 MHZ, CDCl₃ : 8.27 (d, 1H), 7.75 (b,1H), 7.31 (d, 1H), 7.10 (m, 2H), 7.08 (d, d, 1H), 6.93 (d, 1H), 6.85 (m,2H), 5.00 (t, 1H), 4.63 (AB system, 2 H), 3.81 (S, 3H), 3.43 and 2.80(d, d/d, d, 2H), 2.81 (m, 1H), 2.93 and 2.51 (d, d/d, d, 2H). 1,04 (d,3H)].

EXAMPLE 2

With stirring, a mixture of 2.0 g of2'-hydroxy-5'-[(R,S)-1-hydroxy-2-[[(R,S)-p-methoxy-α-methylphenylethyl]amino]ethyl]formanilide(racemic mixture of R,R- and S,S-enantiomers), 200 ml of2,2-dimethoxypropane and 6.0 g ammonium acetate in 140 ml of acetone isrefluxed for 15 hours, then cooled and concentrated under 11 mbar todryness. To the residue are added 10.0 g of potassium hydrogencarbonate,50 ml of ice/water and 50 ml of methylene chloride. After shakingvigorously, the organic phase is separated, washed with 10 ml of 2Npotassium hydrogencarbonate and with 10 ml of brine, dried overmagnesium sulfate, and concentrated by evaporation at 40° C./11 mbar.The residue is flash chromatographed on 70 g of silica gel. Thefractions 1-8, each eluted with 100 ml of methylene chloride/methanol(98:2), are discarded. The fractions 9-14, each eluted with 100 ml ofmethylene chloride/methanol (98:2), are combined and concentrated byevaporation at 40° C./11 mbar. The residue, the racemic mixture of2,2-di-methyl-(5R)-5-(3-formylamino-4-hydroxyphenyl)- 3-[(2R)-1-(4-methoxyphenyl)prop-2-yl]oxazolidine and2,2-dimethyl-(5S)-5-(3-formylamino-4-hydroxyphenyl)-3-[(2S)-1-(4-methoxyphenyl)prop-2-yl]oxazolidine, is obtained as an amorphouspowder. [¹ NMR(400 MHZ, CD Cl₃ ; 8.42 (b, 1H), 8.29 (b, 1H), 7.66 (d, b,1H), 7.10 (m, 2H), 6.87 (m, 2H), 6.81 (d, d, 1H), 6.57 (d, 1H), 4.84 (t,1H), 3.82 (s, 3H), 3.10 . . . 2.66 (m, 5H), 1.28 and 1.11 (2s, 2×3H),1.18 (d, 3H)].

EXAMPLE 3

The RR- and SS-enantiomers of the racemic mixture obtained according toExample 1 are obtained as follows: 20 μl of a 0.1% solution of theracemic mixture of Example 1 are injected into a chiral "CHIRALCEL OJ"(Daicel Chemical Industries, Japan) HPLC column. The carrier materialconsists of silica gel loaded with para-methylbenzoyl cellulose. At aram of flow of 1 ml/min and with an eluant consisting of hexane (85 vol%) and 2-propanol (15 vol %), the enantiomers are separated with aseparation factor of α=1.27.

EXAMPLE 4

20 μl of a 1% solution of the racemic mixture obtained according toExample 1 are injected into a chiral meta-methylbenzoyl cellulose(preparation in accordance with EP-A-0 316 270"U.S. Pat. No. 5,066,793and U.S. Pat. No. 5,091,520"). HPLC column. At a rate of flow of 1ml/min and with an eluant consisting of hexane (85 vol %) and 2-propanol(15 vol %), the enantiomers are separated with a separation factor ofα=1.18.

EXAMPLE 5

With stirring, 22 μl of 37% aqueous formaldehyde are added at roomtemperature to a solution of 99.5 mg of (-)-2'-hydroxy-5'-(R)- 1-hydroxy-2-[[(R)-p-methoxy-α-methylphenethyl]amino]ethyl]formanilide(R,R-enantiomer) in 3 ml of methylene chloride. The mixture is stirredfor 15 hours at 5°-15° C., wherupon a solution forms. The solution isdiluted with 3 ml of methylene chloride, the methylene chloride phase iswashed with water (2×2 ml), dried over magnesium sulfate andconcentrated by evaporation at 40° C./20 mbar. The residue is dried at25° C./0.1 mbar for 15 hours, giving(-)-(5R)-5-(3-formylamino-4-hydroxyphenyl)-3-[(2R)-1-(4-methoxyphenyl)prop-2-yl]-oxazolidineas a white amorphous solid. [¹ H-NMR (400 MHZ, CD₂ Cl₂ : 8.24 (d, 1H),7.70 (b,1H), 7.21 (d, 1H), 7.10 (m,2H), 7.09 (d,d,1 H), 6.93 (d. 1H),6.83 (m,2H), 4.94 (+,1H), 4,57 (AB,2H), 3.78 (s,3H), 3.40 und 2.75(2d,d,2H), 2.88 und 2,50 (2d,d,2H), 2.79 (m, 1H),1.00 (d,3H)].

[α]²⁰ _(D) =-13.1±1.9° (c=0.518, MeOH)

EXAMPLE 6

With stirring, 33.28 μl of 37% aqueous formaldehyde are added at 5°-15°C. to a solution of 151 mg of(-)-2'-hydroxy-5'-(S)-1-hydroxy-2-[[(S)-p-methoxy-α-methylphenethyl]amino]ethyl]formanilide(S,S enantiomer) in 4.5 ml of methylene chloride. The mixture is stirredfor 15 hours at 5°-15° C., whereupon a solution forms. The solution isdiluted with 4 ml of methylene chloride, the methylene chloride phase iswashed with water (2×3 ml), dried over magnesium sulfate andconcentrated by evaporation at 40° C./15 mbar. The residue is dried at25° C./0.1 mbar for 15 hours, giving(-)-(5S)-5-(-3-formylamino-4-hydroxyphenyl)-3-[(2S)-1-(4-methoxyphenyl)prop-2-yl]oxazolidineas an amorphous powder. [¹ H-NMR (400 MHZ, CD₂ Cl₂)]: identical with thespectrum of the compound of Example 5.

[α]²⁰ _(D) =+17.3±1.8° (c=0.550, MeOH)

Analytical determination of the optical purity of the enantiomers

The analytic determination of the purity of the enantiomers (R,R)(Example 5) and (S,S) (Example 6) was made by HPLC on the chiral column(0.46 cm×25 cm) Chiracel OJ (Daicel Chemical Industries, Japan) with amixture of hexane (85 vol %) and ethanol (15 vol %) as eluant, and at arate of flow of 1 mil/min. The chromatography apparatus consists of apump (Gilson, Modell 303), an autosampler (Shimadzu SLC-6B9), a variableUV detector (Perkin-Elmer LC-95) and a data recording system (MetrohmAG, IC-Metrodata 7 14). 20 microlitres of a 0.1% solution (in ethanol)of the individual enantiomers were injected into the column and thefollowing results were obtained (detection at 240 nm): (+) (S,S)enantiomer (compound of Example 6), retention time 93.31 min, ee>99.9%;(-) (R,R) enantiomer (compound of Example 5), retention time 115.89 min,ee>99.9%.

What is claimed is:
 1. A compound of formula (I) ##STR5## wherein R₁ andR₂ are simultaneously hydrogen or both are the same lower alkyl radicalor together are 4- to 7-membered lower alkylene, or a pharmaceuticallyacceptable salt thereof in racemic or chiral form.
 2. A compound offormula I according to claim 1, wherein R₁ and R₂ are simultaneouslyhydrogen or both are the same lower alkyl radical or together are 4- to5-membered lower alkylene, or a pharmaceutically acceptable salt thereofin racemic or chiral form.
 3. A compound of formula I according to claim1, wherein R₁ and R₂ are simultaneously hydrogen or both simultaneouslyare methyl or ethyl, or a pharmaceutically acceptable salt thereof inracemic or chiral form.
 4. A compound of formula I according to claim 1,wherein R₁ and R₂ are simultaneously hydrogen, or a pharmaceuticallyacceptable salt thereof in racemic or chiral form.
 5. The compound ofclaim 1 which is selected from the group consisting of (a)(5R)-5-(3-Formylamino-4-hydroxyphenyl)-3-[(2R)-1-(4-methoxyphenyl)prop-2-yl]oxazolidine,(b)(5S)-5-(3-Formylamino-4-hydroxyphenyl)-3-[(2S)-1-(4-methoxyphenyl)prop-2-yl]oxazolidine,and (c)the racemate of(5R)-5-(3-formylamino-4-hydroxyphenyl)-3-[(2R)-1-(4-methoxyphenyl)prop-2-yl]oxazolidine,and (5S)-5-(3-formylamino-4-hydroxyphenyl)-3-[(2S)-1-(4-methoxyphenyl)prop-2-yl]oxazolidine,or a pharmaceutically acceptable salt thereof.
 6. A method ofstimulating beta-adrenergic receptors in an animal in need thereofcomprising administering to said animal a beta-adrenergic receptorstimulating amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof in racemic or in chiral form.
 7. Apharmaceutical composition for the stimulation of beta-adrenergicreceptors in an animal comprising a beta-adrenergic receptor stimulatingeffective mount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, in racemic or in chiral form, and apharmaceutically acceptable carrier therefor.